[go: up one dir, main page]

US8206621B2 - Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix - Google Patents

Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix Download PDF

Info

Publication number
US8206621B2
US8206621B2 US10/562,707 US56270705A US8206621B2 US 8206621 B2 US8206621 B2 US 8206621B2 US 56270705 A US56270705 A US 56270705A US 8206621 B2 US8206621 B2 US 8206621B2
Authority
US
United States
Prior art keywords
plga
weight
ethanol
plasticized
temperature
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US10/562,707
Other versions
US20060171987A1 (en
Inventor
Patrice Mauriac
Pierre Marion
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mediolanum Pharmaceuticals Ltd
Original Assignee
Mediolanum Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mediolanum Pharmaceuticals Ltd filed Critical Mediolanum Pharmaceuticals Ltd
Publication of US20060171987A1 publication Critical patent/US20060171987A1/en
Assigned to MEDIOLANUM PHARMACEUTICALS LTD. reassignment MEDIOLANUM PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MARION, PIERRE, MAURIAC, PATRICE
Application granted granted Critical
Publication of US8206621B2 publication Critical patent/US8206621B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/141—Plasticizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices

Definitions

  • the present invention relates to the use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix.
  • the extrusion temperature of PLGA is higher than 75° C. Typically the temperature during extrusion must be 40-50° C. above the Tg of the polymer to be extruded.
  • thermolabile active principle dispersed in a polylactic-glycolic acid (PLGA) matrix.
  • the extrusion temperature must be lowered.
  • the use of a plasticizer is widespread which allows the flexibility and the workability of the polymer to be increased following the reduction of the Tg thereof.
  • the amount of plasticizer to be added to the polymer varies as a function of the desired effect.
  • plasticizers are organic synthetic compounds; in most cases they are esters such as adipates and phthalates. These types of products are not biocompatible and therefore cannot be used for subcutaneous implants for application to man and to mammals in general.
  • plasticizers such as triacetin, N-methyl-2-pyrrolidone, glycerol and formaldehyde, their toxicity to man and to mammals has not been fully ascertained.
  • ethanol while being a volatile substance diffuses rapidly and in a homogeneous manner in ground PLGA at a temperature higher than the Tg and lower than the boiling point of ethanol and therefore subcutaneous implants using ethanol as external plasticizing agent can be prepared.
  • external plasticizer means a plasticizing agent to be used in the process of preparing the subcutaneous implant by extrusion, but in a phase previous to the aforesaid preparation, or rather in the preparation phase of the “plasticized” polymer which will be subsequently used in the preparation of the subcutaneous implant.
  • a further aspect of the present invention is therefore a plasticized PLGA containing ethanol as plasticizing agent.
  • This plasticized polymer is therefore prepared using a process which comprises the following stages:
  • a further aspect of the present invention is a subcutaneous implant comprising an active principle dispersed in a matrix based on PLGA plasticized with ethanol according to the present invention.
  • the plasticized PLGA of the present invention generally contains ethanol in concentrations between 2 and 15%, preferably between 3 and 10%, and even more preferably between 5 and 10% by weight on the weight of PLGA.
  • the Applicant has in fact found that by using plasticized PLGA containing ethanol at concentrations between 2% and 3% by weight, the Tg of the polymer and consequently the extrusion temperature can be reduced to temperatures lower than 70° C.; by using ethanol at concentrations higher than between 3 and 4% by weight, this temperature can be reduced to values lower than 60° C.
  • the extrusion temperature can be reduced to 40° C. (i.e. a temperature compatible with most thermolabile biological active principles).
  • the plasticized polymer according to the present invention therefore contains ethanol in concentrations preferably between 5 and 10%, when used for preparing compositions for subcutaneous implants containing thermolabile active principles.
  • the amount of ethanol added is equal to 10 parts by weight per parts by weight of PLGA.
  • stage (c) drying is conducted until obtaining a concentration of ethanol in PLGA preferably comprised between 10 and 30%, more preferably 20% by weight/PLGA weight.
  • drying in step (c) is carried out under an air stream at a temperature comprised between 20 and 25° C.
  • the temperature of grinding in stage (d), (e) and (g) is preferably ⁇ 10° C., while in stage (e) the weight ratio of PLGA originating from stage (d)/PLGA as such is preferably between 16:84 and 40:60.
  • stage (e) By increasing in stage (e) the concentration by weight of PLGA treated with ethanol with respect to the untreated PLGA, the extrusion temperature of the subsequent subcutaneous implant preparation phase is reduced.
  • the subcutaneous implants are prepared by a process comprising the following stages:
  • stage (i) extruding the ground product originating from stage (i) at a temperature less than 70° C., preferably less than 60° C.
  • the extrusion temperature in stage (ii) is about 40° C.
  • thermolabile active principles means active principles which must be stored at low temperature and in particular proteins (hormones, growth factors, enzymes etc), vaccines, antibodies and vectors for genic therapy.
  • the polymer plasticized with ethanol according to the present invention can also be used for preparing subcutaneous implants containing non-thermolabile active principles, however in any event as a precaution it is preferable not to subject them to sudden temperature changes.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 40:60 and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 8% mass/mass.
  • the powdered mixture thus obtained was extruded at 40° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 6.6 ⁇ 10 6 IU.
  • PLGA having the same characteristics as the one described in the Example 1 is ground until a particle size of less than 250 ⁇ m is obtained.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 32.5:67.5 and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 6.5% mass/mass.
  • the active principle consisting of the protein r-Hu-G-CSF having the same characteristics that the one described in the Example 1 and the plasticized polymer (PLGA) were mixed intimately at ⁇ 10° C. in a weight ratio of 30:70 respectively.
  • the powdered mixture thus obtained was extruded at 50° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 6.6 ⁇ 10 6 IU.
  • PLGA having the same characteristics as the one described in the Example 1 is ground until a particle size of less than 250 ⁇ m is obtained.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 16:84 and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 3.2% mass/mass.
  • the active principle consisting of the protein r-Hu-G-CSF having the same characteristics as the one described in the Example 1 and the plasticized polymer (PLGA) were mixed intimately at ⁇ 10° C. in a weight ratio of 30:70 respectively.
  • the powdered mixture thus obtained was extruded at 60° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 6.6 ⁇ 10 6 IU.
  • PLGA having the following characteristics is ground until a particle size of less than 250 ⁇ m is obtained.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 40:60, and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 8% mass/mass.
  • the powdered mixture thus obtained was extruded at 40° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 1.8 IU.
  • PLGA having the same characteristics as the one described in the Example 4 is ground until a particle size of less than 250 ⁇ m is obtained.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 32.5:67.5 and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 6.5% mass/mass.
  • the active principle consisting of the protein r-Hu-GH having the same characteristics as the one described in the Example 4 and the plasticized polymer (PLGA) were mixed intimately at ⁇ 10° C. in a weight ratio of 30:70 respectively.
  • the powdered mixture thus obtained was extruded at 50° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 1.8 IU.
  • PLGA having the same characteristics as the one described in the Example 4 is ground until a particle size of less than 250 ⁇ m is obtained.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 16:84 and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 3.2% mass/mass.
  • the active principle consisting of the protein r-Hu-G-CSF having the same characteristics as the one described in the Example 4 and the plasticized polymer (PLGA) were mixed intimately at ⁇ 10° C. in a weight ratio of 30:70 respectively.
  • the powdered mixture thus obtained was extruded at 60° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 1.8 IU.
  • PLGA having the following characteristics is ground until a particle size of less than 250 ⁇ m is obtained.
  • the ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
  • the polymer thus obtained is mixed at ⁇ 10° C. with the same untreated type of polymer as such in a weight ratio of 40:60 and the said mixture is then extruded at 75° C.
  • the extruded product is then ground at ⁇ 10° C. to obtain the plasticized PLGA with an ethanol content of 8% mass/mass.
  • the active principle consisting of the protein Interferon alfa-2a having the following characteristics:
  • the powdered mixture thus obtained was extruded at 40° C.
  • the extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 40 ⁇ 10 6 IU.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thermotherapy And Cooling Therapy Devices (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

A plasticized polymer of PLGA employing ethanol as the plasticizing agent prepared at a temperature higher than the Tg and lower than the boiling point of ethanol can be used in subcutaneous implants containing active ingredients therein.

Description

FIELD OF THE INVENTION
The present invention relates to the use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix.
STATE OF THE ART
In the current state of the art the extrusion temperature of PLGA is higher than 75° C. Typically the temperature during extrusion must be 40-50° C. above the Tg of the polymer to be extruded.
With this type of technique it is not possible to prepare subcutaneous implants containing a thermolabile active principle dispersed in a polylactic-glycolic acid (PLGA) matrix.
To use such a technique to prepare subcutaneous implants with active principles of this type, the extrusion temperature must be lowered. In general to lower the extrusion temperature the use of a plasticizer is widespread which allows the flexibility and the workability of the polymer to be increased following the reduction of the Tg thereof. The amount of plasticizer to be added to the polymer varies as a function of the desired effect.
An essential requirement for a plasticizer is non-volatility. Currently modern plasticizers are organic synthetic compounds; in most cases they are esters such as adipates and phthalates. These types of products are not biocompatible and therefore cannot be used for subcutaneous implants for application to man and to mammals in general.
For other types of plasticizers such as triacetin, N-methyl-2-pyrrolidone, glycerol and formaldehyde, their toxicity to man and to mammals has not been fully ascertained.
In preparing said type of subcutaneous implants the requirement was therefore felt for a plasticizer able to reduce the extrusion temperature of PLGA which did not present the drawbacks of the state of the art and was non-toxic.
SUMMARY OF THE INVENTION
In particular the Applicant has found that ethanol while being a volatile substance diffuses rapidly and in a homogeneous manner in ground PLGA at a temperature higher than the Tg and lower than the boiling point of ethanol and therefore subcutaneous implants using ethanol as external plasticizing agent can be prepared.
The term “external plasticizer” means a plasticizing agent to be used in the process of preparing the subcutaneous implant by extrusion, but in a phase previous to the aforesaid preparation, or rather in the preparation phase of the “plasticized” polymer which will be subsequently used in the preparation of the subcutaneous implant.
A further aspect of the present invention is therefore a plasticized PLGA containing ethanol as plasticizing agent.
This plasticized polymer is therefore prepared using a process which comprises the following stages:
  • a) grinding PLGA to obtain a ground product in which the particles have dimensions less than 250 μm;
  • b) adding ethanol to the ground product obtained in the preceding stage in concentrations between 5 and 20 parts by weight/weight of PLGA and then heating the mixture obtained to a temperature between 45 and 65° C., until a viscous and stable gel is obtained;
  • c) drying the gel obtained in step (b)
  • d) grinding the dried product coming from step (c) at a temperature between −20 and +5° C.;
  • e) optionally mixing the product originating from the preceding stage with PLGA as such which has been previously ground until a ground product of dimensions less than 250 μm is obtained, in weight ratios between 10:90 and 99:1 respectively, at a temperature between −20 and +5° C.;
  • f) extruding the aforesaid mixture at 75° C.;
  • g) grinding the extruded product at a temperature between −20° C. and +5° C. to obtain the PLGA plasticized with ethanol according to the present invention.
A further aspect of the present invention is a subcutaneous implant comprising an active principle dispersed in a matrix based on PLGA plasticized with ethanol according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The plasticized PLGA of the present invention generally contains ethanol in concentrations between 2 and 15%, preferably between 3 and 10%, and even more preferably between 5 and 10% by weight on the weight of PLGA.
The Applicant has in fact found that by using plasticized PLGA containing ethanol at concentrations between 2% and 3% by weight, the Tg of the polymer and consequently the extrusion temperature can be reduced to temperatures lower than 70° C.; by using ethanol at concentrations higher than between 3 and 4% by weight, this temperature can be reduced to values lower than 60° C.
The Applicant has also found that using ethanol at concentrations between 5 and 10% on the weight of plasticized polymer, the extrusion temperature can be reduced to 40° C. (i.e. a temperature compatible with most thermolabile biological active principles).
The plasticized polymer according to the present invention therefore contains ethanol in concentrations preferably between 5 and 10%, when used for preparing compositions for subcutaneous implants containing thermolabile active principles. Preferably in stage (b) the amount of ethanol added is equal to 10 parts by weight per parts by weight of PLGA.
In stage (c) drying is conducted until obtaining a concentration of ethanol in PLGA preferably comprised between 10 and 30%, more preferably 20% by weight/PLGA weight. Preferably drying in step (c) is carried out under an air stream at a temperature comprised between 20 and 25° C.
The temperature of grinding in stage (d), (e) and (g) is preferably −10° C., while in stage (e) the weight ratio of PLGA originating from stage (d)/PLGA as such is preferably between 16:84 and 40:60.
By increasing in stage (e) the concentration by weight of PLGA treated with ethanol with respect to the untreated PLGA, the extrusion temperature of the subsequent subcutaneous implant preparation phase is reduced.
The subcutaneous implants, a further aspect of the present invention, are prepared by a process comprising the following stages:
i) mixing the active principle with the plasticized PLGA of the present invention, at a temperature between −20° C. and +5° C.
ii) extruding the ground product originating from stage (i) at a temperature less than 70° C., preferably less than 60° C.
As stated above, when the plasticized polymer used in stage (i) contains between 5 and 10% of ethanol, the extrusion temperature in stage (ii) is about 40° C.
In this case the aforesaid process is particularly suitable for preparing subcutaneous implants comprising thermolabile active principles. The term “thermolabile active principles” means active principles which must be stored at low temperature and in particular proteins (hormones, growth factors, enzymes etc), vaccines, antibodies and vectors for genic therapy.
The polymer plasticized with ethanol according to the present invention can also be used for preparing subcutaneous implants containing non-thermolabile active principles, however in any event as a precaution it is preferable not to subject them to sudden temperature changes.
Some illustrative but non-limitative examples of the preparation of plasticized polymer containing ethanol of the present invention together with the preparation of the subcutaneous implant of the present invention containing PLGA plasticized with ethanol and containing a thermolabile active principle are reported herein below.
EXAMPLE 1 Preparation of Subcutaneous Implants Containing Recombinant Human Granulocyte Colony Stimulating Factor (r-Hu-G-CSF)
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the following characteristics:
    • inherent viscosity 0.19 dl/g measured at 25° C. in chloroform (c=0.1 g/dl),
    • Lactide/Glycolide Molar ratio: 53/47,
    • Tg: 40° C.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% weight/weight.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 40:60 and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 8% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein r-Hu-G-CSF having the following characteristics:
    • Protein content (Colorimetry—Bradford): 2.1 to 2.6% mass/mass,
    • Biological potency (In vitro—Std WHO #88/502): 21 to 31×106 IU/mg of protein,
    • Excipients:
    • Mannitol/Polysorbate 80/Sodium Phosphate monobasic/Sodium Phosphate Dibasic Dodecahydrated/Human Albumin (93.4%/0.01%/1.9%/0.5%/1.9% mass/mass respectively)
      and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 31:69 respectively.
The powdered mixture thus obtained was extruded at 40° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 6.6×106 IU.
EXAMPLE 2 Preparation of Subcutaneous Implants Containing Recombinant Human Granulocyte Colony Stimulating Factor (r-Hu-G-CSF)
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the same characteristics as the one described in the Example 1 is ground until a particle size of less than 250 μm is obtained.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% weight/weight.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 32.5:67.5 and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 6.5% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein r-Hu-G-CSF having the same characteristics that the one described in the Example 1 and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 30:70 respectively.
The powdered mixture thus obtained was extruded at 50° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 6.6×106 IU.
EXAMPLE 3 Preparation of Subcutaneous Implants Containing Recombinant Human Granulocyte Colony Stimulating Factor (r-Hu-G-CSF)
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the same characteristics as the one described in the Example 1 is ground until a particle size of less than 250 μm is obtained.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% mass/mass.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 16:84 and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 3.2% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein r-Hu-G-CSF having the same characteristics as the one described in the Example 1 and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 30:70 respectively.
The powdered mixture thus obtained was extruded at 60° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 6.6×106 IU.
EXAMPLE 4 Preparation of Subcutaneous Implants Containing Recombinant Human Growth Hormone (r-Hu-GH)
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the following characteristics is ground until a particle size of less than 250 μm is obtained.
    • inherent viscosity 0.19 dl/g measured at 25° C. in chloroform (c=0.1 g/dl),
    • Lactide/Glycolide Molar ratio: 53/47,
    • Tg: 40° C.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% mass/mass.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 40:60, and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 8% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein r-Hu-GH having the following characteristics:
    • Related proteins (Liquid Chromatography according to the monograph “Somatropin”—Nr 0951 of the 4th Edition of the European Pharmacopoeia): maximum 13% (peaks area),
    • Dimer and related substances of higher molecular mass (Size Exclusion Chromatography according to the monograph “Somatropin”—Nr 0951 of the 4th Edition of the European Pharmacopoeia): maximum 6% (peaks area),
    • Protein Content (Size Exclusion Chromatography according to the monograph “Somatropin”—Nr 0951 of the 4th Edition of the European Pharmacopoeia): 4.5 to 5.3% mass/mass,
    • Biological potency (Size Exclusion Chromatography according to the monograph “Somatropin”—Nr 0951 of the 4th Edition of the European Pharmacopoeia): 2.7 to 3.2 IU/mg of protein,
    • Excipients:
      Glycin/Sodium Phosphate monobasic/Sodium Phosphate Dibasic Dodecahydrated
      (91.4%/1.0%/2.5% mass/mass respectively)
      and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 30:70 respectively.
The powdered mixture thus obtained was extruded at 40° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 1.8 IU.
The integrity of the protein within the depots was examined through the following analytical package:
    • Related proteins by Liquid Chromatography according to the monograph “Somatropin” (Nr 0951) of the 4th Edition of the European Pharmacopoeia,
    • Dimer and related substances of higher molecular mass by Size Exclusion Chromatography according to the monograph “Somatropin” (Nr 0951) of the 4th Edition of the European Pharmacopoeia,
    • Assay by Size Exclusion Chromatography according to the monograph “Somatropin” (Nr 0951) of the 4th Edition of the European Pharmacopoeia.
EXAMPLE 5 Preparation of Subcutaneous Implants Containing Recombinant Human Growth Hormone (r-Hu-GH)
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the same characteristics as the one described in the Example 4 is ground until a particle size of less than 250 μm is obtained.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% mass/mass.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 32.5:67.5 and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 6.5% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein r-Hu-GH having the same characteristics as the one described in the Example 4 and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 30:70 respectively.
The powdered mixture thus obtained was extruded at 50° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 1.8 IU.
The integrity of the protein within the depots was examined through the same analytical package that the one described for Example 4.
EXAMPLE 6 Preparation of Subcutaneous Implants Containing Recombinant Human Growth Hormone (r-Hu-GH)
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the same characteristics as the one described in the Example 4 is ground until a particle size of less than 250 μm is obtained.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% mass/mass.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 16:84 and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 3.2% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein r-Hu-G-CSF having the same characteristics as the one described in the Example 4 and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 30:70 respectively.
The powdered mixture thus obtained was extruded at 60° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 1.8 IU.
EXAMPLE 7 Preparation of Subcutaneous Implants Containing Interferon Alfa-2a
a) Preparation of PLGA Plasticized with Ethanol
PLGA having the following characteristics is ground until a particle size of less than 250 μm is obtained.
    • inherent viscosity 0.19 dl/g measured at 25° C. in chloroform (c=0.1 g/dl),
    • Lactide/Glycolide Molar ratio: 53/47,
    • Tg: 40° C.
The ground product is added to an excess of ethanol until a concentration of PLGA in ethanol equal to 0.12 g/ml is obtained and is placed in a bath of water heated to 45° C. and stirred for 1 minute. The ethanol diffuses into the polymer and forms a viscous gel. This gel is maintained in ethanol for 3 minutes.
This is followed by drying at 20° C. until a PLGA is obtained containing ethanol in a quantity equal to 20% mass/mass.
The polymer thus obtained is mixed at −10° C. with the same untreated type of polymer as such in a weight ratio of 40:60 and the said mixture is then extruded at 75° C.
The extruded product is then ground at −10° C. to obtain the plasticized PLGA with an ethanol content of 8% mass/mass.
b) Preparation of the Subcutaneous Implant
The active principle consisting of the protein Interferon alfa-2a having the following characteristics:
    • Related proteins (Liquid Chromatography according to the monograph “Interferon alfa-2 Concentrated solution”—Nr 1110 of the 4th Edition of the European Pharmacopoeia): maximum 5% (peaks area),
    • Protein Content: 1.8% mass/mass,
    • Biological potency (Size Exclusion Chromatography according to the monograph “Interferon alfa-2 Concentrated solution”—Nr 1110 of the 4th Edition of the European Pharmacopoeia): 2.3×108 IU/mg of protein,
    • Excipients:
    • Sodium Acetate/Sodium Chloride/Trehalose (5.9%/8.4%/83.9% mass/mass respectively)
      and the plasticized polymer (PLGA) were mixed intimately at −10° C. in a weight ratio of 25:75 respectively.
The powdered mixture thus obtained was extruded at 40° C. The extruded product thus obtained (1.5 mm in diameter) was then cut to a length of 18 mm to form cylindrical deposits each weighing 40 mg and each containing the protein in a quantity equal to 40×106 IU.
The integrity of the protein within the depots was examined through the following analytical package:
    • Related proteins by Liquid Chromatography according to the monograph “Interferon alfa-2 Concentrated solution” (Nr 1110) of the 4th Edition of the European Pharmacopoeia.

Claims (17)

1. PLGA plasticized with ethanol, obtained by a process comprising the following steps:
a) grinding PLGA to obtain a ground product in which the particles have dimensions less than 250 μm;
b) adding ethanol to the ground product obtained in the preceding step in concentrations between 5 and 20 parts by weight/weight of PLGA and heating the mixture obtained to a temperature between 45 and 65° C., until a viscous and stable gel is obtained;
c) drying the product coming from step (b),
d) grinding the dried product obtained at a temperature ranging from −20 and +5° C.;
f) extruding the aforesaid product at 75° C., and
g) grinding the extruded product at a temperature between −20° C. and +5° C.,
said process optionally comprising a step e), to be performed before step f), of mixing the product coming from step d) with untreated PLGA, which has been previously ground until a ground product of particle size less than 250 μm is obtained, in a weight ratio of product coming from step d)/untreated PLGA between 10:90 and 99:1, at a temperature between −20 and +5° C.
2. Plasticized PLGA as claimed in claim 1 containing ethanol in concentrations between 2 and 15% by weight on the weight of PLGA.
3. Plasticized PLGA as claimed in claim 2 wherein said ethanol concentrations are between 3 and 10% by weight on the weight of PLGA.
4. Plasticized PLGA as claimed in claim 2 wherein said concentrations are between 5 and 10% by weight on the weight of PLGA.
5. Plasticised PLGA according to claim 1, wherein in step (b) the ethanol is added in a quantity of 10 parts by weight/weight of PLGA.
6. Plasticised PLGA according to claim 1, wherein in step (d) the drying is conducted until obtaining an ethanol concentration in PLGA between 10 and 30%/by weight/PLGA weight.
7. Plasticised PLGA according to claim 6 wherein said ethanol concentration is 20% by weight/PLGA weight.
8. Plasticised PLGA according to claim 6, wherein said drying is carried out at a temperature between 20 and 25° C. under an air stream.
9. Plasticised PLGA as claimed in claim 1, wherein the grinding temperature in step (d), (e) and (g) is −10° C.
10. Plasticised PLGA as claimed in claim 1 wherein in step (e) the weight ratio of PLGA coming from step (d)/untreated PLGA is between 16:84 and 40:60.
11. Subcutaneous implants obtained by extrusion, containing an active principle dispersed in PLGA plasticized with ethanol as claimed in claim 1.
12. Subcutaneous implants as claimed in claim 11 containing thermolabile active principles.
13. Subcutaneous implants as claimed in claim 12, wherein said thermolabile active principles are selected from the group consisting of proteins, vaccines, antibodies and vectors for genic therapy.
14. A process for preparing a subcutaneous implant obtained by extrusion containing an active principle dispersed in PLGA plasticized with ethanol according to claim 1, comprising the following steps:
i) mixing the active principle with the plasticized PLGA as claimed in claim 1, at a temperature between −20° C. and +5° C.,
ii) extruding the ground product originating from step (i) at a temperature less than 70° C.
15. The process as claimed in claim 14, wherein the temperature of step (i) is −10° C.
16. The process as claimed in claim 14 wherein the temperature of step (ii) is less than 60° C. when plasticized PLGA containing when plasticized PLGA containing ethanol at concentrations between 3 and 4% by weight on the weight of PLGA is used in step (i).
17. The process as claimed in claim 15, wherein the temperature of step (ii) is equal to 40° C., when plasticized PLGA containing ethanol at concentrations between 5 and 10% by weight/weight of PLGA is used.
US10/562,707 2003-06-26 2004-06-24 Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix Expired - Fee Related US8206621B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITMI2003A1302 2003-06-26
ITMI2003A001302 2003-06-26
IT001302A ITMI20031302A1 (en) 2003-06-26 2003-06-26 USE OF ETHANOL AS A PLASTICIZER TO PREPARE SUBCUTANEOUS IMPLANTS CONTAINING THERMALABLE ACTIVE PRINCIPLES DISPERSED IN A PLGA MATRIX.
PCT/EP2004/051226 WO2005000277A1 (en) 2003-06-26 2004-06-24 Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a plga matrix

Publications (2)

Publication Number Publication Date
US20060171987A1 US20060171987A1 (en) 2006-08-03
US8206621B2 true US8206621B2 (en) 2012-06-26

Family

ID=30131301

Family Applications (1)

Application Number Title Priority Date Filing Date
US10/562,707 Expired - Fee Related US8206621B2 (en) 2003-06-26 2004-06-24 Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix

Country Status (17)

Country Link
US (1) US8206621B2 (en)
EP (1) EP1638534B1 (en)
JP (1) JP2009513165A (en)
KR (1) KR101143771B1 (en)
CN (1) CN100509060C (en)
AT (1) ATE398447T1 (en)
AU (1) AU2004251456B2 (en)
BR (1) BRPI0411759A (en)
CA (1) CA2530117C (en)
CY (1) CY1108346T1 (en)
DE (1) DE602004014496D1 (en)
ES (1) ES2308195T3 (en)
IT (1) ITMI20031302A1 (en)
MX (1) MXPA05013697A (en)
PL (1) PL1638534T3 (en)
PT (1) PT1638534E (en)
WO (1) WO2005000277A1 (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7666445B2 (en) 2000-10-20 2010-02-23 The Trustees Of The University Of Pennsylvania Polymer-based surgically implantable haloperidol delivery systems and methods for their production and use
WO2007011955A2 (en) * 2005-07-18 2007-01-25 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
US8329203B2 (en) 2004-01-12 2012-12-11 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
US8221778B2 (en) 2005-01-12 2012-07-17 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
ES2432556T3 (en) 2004-08-04 2013-12-04 Evonik Corporation Methods for manufacturing supply devices and their devices
ITMI20061539A1 (en) * 2006-08-02 2008-02-03 Mediolanum Pharmaceuticals Ltd SUBCUTANEOUS PLANTS ABLE TO RELEASE THE ACTIVE PRINCIPLE FOR A PROLONGED PERIOD OF TIME
DE602007008125D1 (en) 2006-10-31 2010-09-09 Surmodics Pharmaceuticals Inc BALL-SHAPED POLYMER PARTICLES
JP5502751B2 (en) 2007-12-20 2014-05-28 エボニック コーポレイション Process for preparing microparticles with low residual solvent concentration
US9498431B2 (en) * 2008-12-10 2016-11-22 Jianjian Xu Controlled releasing composition
WO2012003210A1 (en) * 2010-06-30 2012-01-05 Surmodics Pharmaceuticals, Inc. Implant processing methods for thermally labile and other bioactive agents and implants prepared from same
GB201314312D0 (en) * 2013-08-09 2013-09-25 Regentec Ltd Composition and delivery system
CN103623415B (en) * 2013-12-04 2015-03-25 北京诺康达医药科技有限公司 PLGA and ethyl alcohol compound used for biological polypeptide preparation
US20170231916A1 (en) * 2014-08-04 2017-08-17 Janssen Sciences Ireland Uc Compacted solid dosage form
GB201702475D0 (en) * 2017-02-15 2017-03-29 Locate Therapeutics Ltd Tissue scaffold and scaffold composition
EP3459527B1 (en) * 2017-09-20 2022-11-23 Tillotts Pharma Ag Method for preparing a solid dosage form comprising antibodies by wet granulation, extrusion and spheronization

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5520923A (en) 1994-09-19 1996-05-28 Genetics Institute, Inc. Formulations for delivery of osteogenic proteins
WO2000033809A1 (en) 1998-12-10 2000-06-15 Mediolanum Farmaceutici S.P.A. Compositions containing a peptide and polylactic-glycolic acid suitable for preparing subcutaneous implants with an extended release period
WO2003041685A1 (en) 2001-11-14 2003-05-22 Alza Corporation Injectable depot composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0549629A (en) * 1991-08-23 1993-03-02 Konica Corp Medical radiation image shadow reading device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5520923A (en) 1994-09-19 1996-05-28 Genetics Institute, Inc. Formulations for delivery of osteogenic proteins
WO2000033809A1 (en) 1998-12-10 2000-06-15 Mediolanum Farmaceutici S.P.A. Compositions containing a peptide and polylactic-glycolic acid suitable for preparing subcutaneous implants with an extended release period
WO2003041685A1 (en) 2001-11-14 2003-05-22 Alza Corporation Injectable depot composition

Also Published As

Publication number Publication date
PL1638534T3 (en) 2009-02-27
PT1638534E (en) 2008-09-29
KR20060079146A (en) 2006-07-05
AU2004251456B2 (en) 2009-12-03
HK1089954A1 (en) 2006-12-15
ES2308195T3 (en) 2008-12-01
DE602004014496D1 (en) 2008-07-31
CY1108346T1 (en) 2014-02-12
ITMI20031302A1 (en) 2004-12-27
KR101143771B1 (en) 2012-05-11
EP1638534A1 (en) 2006-03-29
AU2004251456A1 (en) 2005-01-06
EP1638534B1 (en) 2008-06-18
CA2530117C (en) 2012-01-10
BRPI0411759A (en) 2006-08-08
CA2530117A1 (en) 2005-01-06
WO2005000277A1 (en) 2005-01-06
ITMI20031302A0 (en) 2003-06-26
MXPA05013697A (en) 2006-05-17
ATE398447T1 (en) 2008-07-15
US20060171987A1 (en) 2006-08-03
CN100509060C (en) 2009-07-08
JP2009513165A (en) 2009-04-02
CN1812770A (en) 2006-08-02

Similar Documents

Publication Publication Date Title
US8206621B2 (en) Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a PLGA matrix
DE69713378T2 (en) STABLE PROTEIN AND NUCLEIC ACID FORMULATIONS USING NON-AQUE, WATER-FREE, APROTIC, HYDROPHOBIC, NON-POLAR VEHICLE WITH LOW REACTIVITY
US5385738A (en) Sustained-release injection
JP3445283B2 (en) Sustained-release composition of drug encapsulated in fine particles of hyaluronic acid
US5081156A (en) Sustained-release preparation
US4985253A (en) Sustained release composition for pharmaceutical substances comprising a silicone elastomer carrier
EP0138216B1 (en) Sustained-release ifn preparation for parenteral administration
US20030166508A1 (en) Biologically active oral preparation that can be site-specific released in colon
JPS61194034A (en) Powdery composition for transnasal administration
EP0302582A1 (en) Drug delivery system and method of making the same
JP2004285079A (en) Sustained-release protein preparation
KR20040058100A (en) Injectable depot compositions and uses thereof
JPH06511263A (en) injectable lecithin gel
JPH10502376A (en) New drug delivery system
EP0140255A2 (en) Sustained-release injections
JPH0761959B2 (en) Silicone elastomer-based sustained release formulation
JPH0512328B2 (en)
RU2083222C1 (en) Method of preparing the enteral preparation containing alpha-interferon and enteral preparation containing alpha-interferon as tablets
HK1089954B (en) Use of ethanol as plasticizer for preparing subcutaneous implants containing thermolabile active principles dispersed in a plga matrix
KR100329336B1 (en) Hyaluronate microparticles for sustained release of a protein drug
CN114794309A (en) Feed additive containing acidifying agent and preparation method and application thereof
JPS60126217A (en) Long-term sustained release pharmaceutical preparation
JPH0372046B2 (en)
JP3182229B2 (en) Animal suspension paste
JPH05246879A (en) Long-term sustained release pharmaceutical

Legal Events

Date Code Title Description
AS Assignment

Owner name: MEDIOLANUM PHARMACEUTICALS LTD., IRELAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MAURIAC, PATRICE;MARION, PIERRE;REEL/FRAME:028280/0870

Effective date: 20041008

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20160626